Imatinib
The clinical drug development of imatinib provides a useful contrast to rofecoxib. Imatinib is a poster-drug for rational drug design.
Chronic Myeloid Leukaemia (CML)
Patients with chronic myeloid leukaemia have a translocated gene, “Abelson” (ABL1) on chromosome 22—at a region called the “breakpoint cluster region” (BCR): BCR-ABL1 an aberrant tyrosine kinase gene
BCR-ABL1 results in proliferation and reduced apoptosis of white blood cells
Without treatment patients with CML have a chronic phase (leukocytosis and/or thrombocytosis); acute phase (increasing, 10–19% myeloblasts, or white blood cells), and blast phase (\(\ge\) 20% myeloblasts or lymphoblasts, …)
Survival without treatment \(\approx\) 5 years; standard treatment interferon-\(\alpha\) (modest benefits, significant toxicity) or allogeneic haematopoietic stem cell transplant (toxicity, limited availability)
The BRC-ABL1 gene is highly specific: if you have the aberrant gene you have, or will develop, CML and if you have CML you will have the aberrant gene.
Imatinib development
Clear target: BRC-ABL1
Test compound libraries for chemicals that inhibit ABL-kinases using high-throughput screening
Optimise for absorption, distribution, metabolism and excretion properties
Imatinib is a orally active compound that inhibits a number of tyrosine kinases (including ABL, PDGFR, KIT, ARG); it was not possible to selectively inhibit BRC-ABL1
Acronyms: PDGFR–platelet-derived growth factor receptor; KIT–proto-oncogene c-Kit; ARG–abl-related gene
Litzow (2008) provides a good background on imatinib development and clinical use.
Pre-clinical information
The specificity of the mechanism for CML and our ability to inhibit it is vital
This specificity provides reasons to expect a tight link between the in vitro results and clinical outcomes in CML
Imatinib was selected for its activity against BCR-ABL and for it’s pharmacokinetic and chemical profile
Imatinib inhibited proliferation of leukaemic cells that expressed BCR-ABL1, but not did not inhibit proliferation of BCR-ABL-negative cells
The questions that arise in the clinical development of imatinib are similar to rofecoxib (and any drug)—but the context is significantly different.
Example Phase I trial in CML (Druker et al. 2001)
Dose escalation trial in chronic phase CML patients in whom interferon-\(\alpha\) treatment had failed.
83 patients successively assigned to 1 of 14 dose cohorts, ranging from 25mg–1000mg per day
53 of the 54 patients on \(\ge\) 300mg/day had a complete haematological response (reduced WBC and platelet count maintained for four weeks). 51 of these patients maintained this response up to 265 days.
Imatinib was generally well-tolerated; MTD was not indentified
Half of the patients assigned to receive 25, 50, 85mg daily were removed within 2 months due to elevated white-cell or platelet counts (Druker et al. 2001).
Phase II trials enrolled larger numbers of patients and demonstrated the efficacy of imatinib in patients with accelerated and blast phase CML.
Key Phase III trial in CML: IRIS (O’Brien et al. 2003)
1106 patients with chronic phase, Ph-positive CML randomised to imatinib or interferon-\(\alpha\) plus cytarabine (cross-over permitted if lack of response)
Primary endpoint: progression (accelerated-phase CML, blast-phase CML, loss of complete haematological response, loss of major cytogenetic response, or an increasing WBC count)
Disease did not progress in 92.1% in the imatinib group and 73.5% of patients in the interferon-\(\alpha\) group at 18 months
Response closely linked to cytogenetic response (quantification of BCR-ABL1 transcript)
IRIS was conducted in 177 hospitals in 16 countries.
Comparing rofecoxib and imatinib
Phase I study population: healthy volunteers versus patients with very poor prognosis
Treatment options: arsenal of anti-inflammatories versus palliative care
Considerably greater experience with compounds like rofecoxib
Specificity of mechanism of action: mallet versus scalpel
Endpoint: measure clinical outcome that is subjective and variable versus surrogate with clear links to important clinical outcomes
References
Druker, B J, M Talpaz, D J Resta, and Et Al. 2001. “Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.” The New England Journal of Medicine 344 (14): 1031–7.
Litzow, Mark R. 2008. “BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients.” In Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response, edited by Federico Innocenti, 377. Humana Pr Inc. http://books.google.com/books?id=QEJyUxTf1AMC.
O’Brien, S G, F Guilhot, R A Larson, I Gathmann, M Baccarani, F Cervantes, J J Cornelissen, et al. 2003. “Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.” New England Journal of Medicine 348 (11): 994–1004.